Antiprogestin method for reducing side effects associated with low dosage HRT and oral contraception

ABSTRACT

Menses regulation and, when desired, contraception is achieved at low doses of estrogen and progestin, which otherwise would create episodes of breakthrough bleeding and/or withdrawal amenorrhea, by periodically inducing menses with an antiprogestin.

This is a continuation-in-part of application Ser. No. 07/843,058, filedMar. 2, 1992, now abandoned, and of PCT Application PCTUS93/01931, filedMar. 2, 1993.

BACKGROUND OF THE INVENTION

This invention relates to a method and kit for regulating menses and/orreducing the side effects, such as unscheduled bleeding, in pre-, para-and post-menopausal females on low dosage estrogen and/or withestrogen-progestin therapy and for achieving oral contraception ingonadal female mammals.

Although inhibition of ovulation in the form of estrogen/progestincombination oral contraceptives has been the most effective strategy forachieving reversible pharmacological fertility control in women, becauseof the known adverse side-effects associated with long termcontraception by this method, especially in women who smoke in the 40-44age group, over the years interest in achieving contraception at lowerestrogen doses has developed.

Thus, during the over 30 year history of combined estrogen/progestinoral contraception, there has been a steady downward adjustment of thedaily estrogen dosage, both for oral contraceptive purposes inpremenopausal female and for estrogen replacement therapy inpost-menopausal females. See, e.g., EP-A-0 253,607, which discloses, asa preferred embodiment, administering to pre-menopausal females daily atablet containing 1 mg of 17β-estradiol and 0.075 ml of levonorgestrelfor 23 or 24 (23-26) days followed by 5 or 4 (2-5) “pill free” orblank-pill days, for a total of 28 days per cycle, and the referencescited therein, the disclosures of all of which are incorporated hereinby reference.

Concurrently, although the progestin component has been lowered somewhatalso, reduced androgenicity has remained an ongoing priority. Together,these adaptations of formulation have been presented in a variety ofregimens, both monophasic and multiphasic. As a result, today's oralcontraceptives are much safer with regard to the incidence and severityof estrogen-linked clotting disorders, as well as the cumulative impactof more “lipid friendly” progestins that maintain high densitylipoprotein cholesterol levels in circulation. See, Spellacy, W N etal.,; “Am J Obstet Gynecol” 1980; 137; 109; Scott, J Z et al., “FertilSteril” 1978; 30:141; Mishell, DR Jr. et al., “J Reprod Med.” 1990; 35(Suppl. 4): 447-481; Speroff L., “Contemp Obstet Gynecol” 1991; 36:65;Meilis G B et al., “Contraception” 1991; 43; 23; and Stamplfer M J,Willett W C et al., “Am J. Obstet Gynecol” 1990; 163: 285.

This evolution of oral contraceptive formulations advanced most rapidlyin Europe and has been steadily emerging in America as well. Indeed, theaccumulating data based on oral contraceptive pills containing only 20to 35 μg of estrogen per day spurred the Food and Drug Administration'sFertility and Maternal Health Drugs Advisory Committee to indicate lowdose oral contraceptives for healthy, non-smoking women during theperimenopausal years (such as ages 35 to 50) [See Mishell (1990) andSperoff (1991)], supra; U.S. Food and Drug Administration, AdvisoryCommittee on Maternal and Reproductive Health, 1989, Rockville, Md.; andRosenberg, L. et al. JAMA 1985; 253:2965. In Japan, oral contraceptivesare now being evaluated for safety and efficacy criteria for the firsttime, with anticipation of general availability to physicians andpatients within about one year.

In addition to maintenance of contraception efficacy when the female isgonadal a principal issue involved when considering lowering the dailydose of estrogen-progestin medications in oral contraceptives evenlower, is avoidance of further erosion in the control of endometrialbleeding. Whereas even the lowest dose oral contraceptive productsavailable now have demonstrated sustained contraception efficacy,overall the incidence of bleeding control problems, which manifestthemselves both in breakthrough bleeding (untimely flow or spotting) orwithdrawal amenorrhea during the “pill free” week (expected menses), hasincreased as estrogen/progestin doses are reduced. See Gray, R H. in“Endometrial Bleeding and Steroidal Contraception”; Diczfalusy E, FraserR S, Webb F T E (Eds). Bathe, England: Pittman Press; 1990: 14-19, andCullbey G. et al., “Contraception” 1982; 26:229. The same problem isassociated with low dosage hormonal replacement therapy (HRT).

OBJECTS OF THE INVENTION

It is an object of this invention to solve the bleeding control problemassociated with low dosage estrogen, and/or of progestin hormonereplacement therapy (HRT).

It is another object of this invention to provide a method for achievingcontraception in a gonadal female mammal at ultra low estrogen and/orprogestin oral doses without the breakthrough bleeding and/or amenorrheawhich is associated therewith.

Another object is to provide such a method which permits a normal mensesand which regulates the onset thereof.

Still another object is to provide such methods in which the medicationis self-administered.

A further object is to provide such methods which do not have the sideeffects associated with conventional or low oral dosageestrogen-progestin oral contraception or hormonal replacement therapy.

Another object is to provide kits for practicing the methods of thisinvention.

Another object is to provide a pharmaceutical composition effective toinduce menses in a female on estrogen/progestin oral contraception orestrogen and/or progestin hormonal replacement therapy (HRT).

Other objects will be apparent to those skilled in the art to which thisinvention pertains.

SUMMARY OF THE INVENTION

In a method aspect, this invention relates to a method of avoiding thebleeding problems associated with administering to a female mammaldosage amounts of an estrogen, alone or in combination with a progestin,low enough to create incidents of breakthrough bleeding and withdrawalamenorrhea, which comprises periodically inducing menses byadministering to the female an amount of an anti-progestin effective toinduce sloughing of accumulated endometrial tissue.

In one article of manufacture aspect, this invention relates to apharmaceutical composition adapted for oral ingestion comprising a unitdosage containing a menses inducing dosage amount of an antiprogestin,arranged to be ingested after ingestion for at least 20, e.g., 20-180,consecutive days of at least 20, e.g., 20-180, unit dosages containingamounts of an estrogen and/or progestin effective to provide HRT inpara- or post-menopausal female but which are too low to avoidbreakthrough bleeding and/or withdrawal amenorrhea. In another articleof manufacture aspect, the amounts of the estrogen or estrogen andprogestin are effective to achieve oral contraception in a gonadalfemale when such amounts have been ingested daily without interruptionfor a least 20 days by a gonadal female.

In another article of manufacture aspect, this invention relates to akit containing and arranged in a conventional manner, e.g., like BerlexLaboratories “Levien 21”, at least 20 oral dosage units, each containingan estrogen and optionally a progestin in some or all of them, inamounts which collectively are effective, when one dosage unit thereofis ingested daily for 20 or more days, to achieve either HRT in a para-or post-menopausal female human being or oral contraception in a gonadalfemale human being, but which promote incidents of breakthrough bleedingand/or withdrawal amenorrhea.

In a first embodiment of the kit aspect of this invention, an additionaloral dosage unit, containing only a menses-inducing amount of anantiprogestin, is positioned so as to be ingested after ingestion of the20 or more estrogen/progestin oral dosage units. In one variation ofthis embodiment of the kit, the number of estrogen/progestin-combinationoral dosage units which precedes the antiprogestin-containing oraldosage units is increased, e.g., to 21 or more, e.g., 21 or up to 180units. In another variation, intended for use on estrogen replacementtherapy by para- and post-menopausal females, the progestin is omittedfrom some or all of the tablets. These variations are for individualswho wish to extend the length of their medically regulated menstrualcycles beyond the usual 4 week term.

In a second embodiment of the kit aspect of this invention, positionedto be taken after the 20 or more oral dosage units of the firstembodiment described above, e.g., like Berlex Laboratories “Levien 28”,are 6 or more placebo oral dosage units to maintain a “one-pill-a-day”regimen and remind the individual when to begin a new cycle ofadministration.

In a third and preferred embodiment of the kit, instead of the 6 or moreplacebo oral dosage units described above, the kit contains 28 or 29 or30 oral dosage units, each of which contains low dosage amounts ofestrogen and progestin corresponding to the first 21 dosage units of thefirst embodiment. In this embodiment, the dosage unit arranged to betaken on the 22nd day also contains a menses inducing amount of theantiprogestin.

DETAILED DESCRIPTION

This invention is based on the discovery that incidents of breakthroughbleeding and withdrawal amenorrhea the frequency of which increase whenoral contraception is achieved employing lower than conventionalestrogen and progestin dosages can be minimized or avoided completely byinducing menses with an anti-progestin, either during the “drug-free”,i.e., estrogen- and progestin-free, week of the monthly cycle of dailyfor about 21 days estrogen and progestin oral administration orpreferably whenever a menses is desired during uninterrupted dailyestrogen or estrogen and progestin administration.

Also, a normal menses can be achieved with an anti-progestin withoutinterrupting a concurrent continuous low dose estrogen/progestin oralcontraceptive regimen. A continuous ultra low dose estrogen/progestinoral contraception regimen in combination with periodic, e.g., at 30, 60or 90 days intervals, administration of an antiprogestin, e.g., RU 486,provides predictable menstrual control.

The physiological rationale for this approach is to maintain a lesserdegree of pharmacologic inhibition of the pituitary-ovarian-uterineaxis, but by an uninterrupted regimen to avoid “follicular escape”. Withtoday's lower dose oral contraceptive products, robust ovarianfollicular growth can resume more quickly during the “pill free”interval than when higher dose pills were used in former decades. Inturn, enhanced endogenous estradiol secretion with rapid endometrialproliferation, all known to accelerate during the “pill-free” 7-dayperiod, results in less intermenstrual breakthrough bleeding, and lesswithdrawn amenorrhea as well. The intermittent administration of theprogesterone antagonist is scheduled so as to ensure sloughing of theaccumulated endometrial tissue at every fourth week or at extendedintervals, e.g., every 60, 90, 120, 150, 180 or more days, withoutpill-free interruption of the oral contraceptive regimen.

The intermittent, i.e., about monthly or longer, e.g., di- ortri-monthly, quarterly or semi-annually, administration of ananti-progestin to induce menses according to this invention avoidsabnormal bleeding problems, e.g., breakthrough bleeding and withdrawalamenorrhea, by maintaining follicular phase level of endogenous serumestradiol at a higher level than that associated with conventional lowdosage estrogen/progestin oral contraception.

In the normal menstrual cycle, progesterone is produced from the corpusluteum created after ovulation. In the contraceptive method of thisinvention, a progestin is administered along with an estrogen, at leasttoward the end of each regulated cycle, e.g., during about the last twoweeks of each cycle, in order to convert proliferative endometrium tothe secretory phase, thereby reducing the risks of endometrialcarcinomas associated with unopposed estrogen action. However, menses isachieved with the anti-progestin alone, irrespective of whether or notadministration of the estrogen and/or the progestin is interruptedduring the menses week of the menstrual cycle when the anti-progestin isadministered.

The daily oral doses of estrogen and progestin which are administeredgenerally are the lowest which will achieve reliable contraception orhormone replacement therapy in women, viz., doses contraceptivelyequivalent to about 5 to 35 mcg. of ethinyl estradiol and about 0.5 to1.5 mg. of norethindrone acetate. The daily doses can be the samethroughout the month or can vary from week to week, as in the case ofBerlex Laboratories “Tri-Levien”, e.g., when a monthly menses isdesired, in which case the doses of both or either can be lowered oreliminated during the menses week of the cycle. However, ifadministration thereof is eliminated or lowered during the menses week,the dosages thereof during the other weeks of the cycle preferably areincreased accordingly, e.g., during the second and especially during thethird weeks to ensure that breakthrough bleeding does not occur prior tomenses.

Similarly, when a monthly menses is not desired, e.g., in the case ofpost-menopausal females, the dosage of the estrogen and/or the progestincan periodically be briefly increased, e.g., at a predetermined periodafter the last menses, above the base-line long term dosage, to suppressisolated instances of breakthrough bleeding as a result of low levels ofestrogen and/or progestin administration over a protracted period oftime.

Examples of progestins which can be employed in this invention aremicronized progesterone (15-50 mg/day), norethindrone and esters, e.g.,acetate, thereof (0.1-0.75 mg/day), norethynodrel (0.3-0.6 mg/day);ethynodiol diacetate (0.3-0.75 mg/day), norgestrel (0.75-0.2 mg) andlevo-norgestrel (0.03-0.1 mg/day), chlormadinone acetate, cyproterone,cyproterone acetate, norethindrone, desogestrel, norgestimate,dihydrospirenone, levonorgestrel, and gestodene (Schering A G, Berlin;U.S. Pat. No. 4,081,537), (equivalent to 0.03-0.15 mg levo-norgestrel.

For a listing of compounds see the articles from the book by B.Runnebaum et al., “Female Contraception: Update and Trends”,Springer-Verlag, Berlin, 1988, pp. 64-90, 109-121, 122-128, and 129-140;which disclose progestationally active compounds. See for example, page65 and pages 68-70 which list various progestins; pages 110 and 111(FIG. 1 and Table 1) which list synthetic progestagens; page 122, FIG. 1which list gestagens; and pages 129-133 (FIGS. 1-10) and page 137, Table2 which list progestagens, or the long acting esters of estriol,described in U.S. Pat. Nos. 4,681,875 and 4,738,957.

Examples of estrogens which can be employed in this invention areethinyl estradiol and estradiol and their esters, e.g., acetate,valerate, benzoate and undecylate, (5-15 mcg/day) mestranol (20-25mcg/day), and conjugated estrogens (5-15 mcg/day).

The progestin and estrogen can be administered in the conventionalmanner by any route that the selected progestin and estrogen is active,e.g., orally, by intramuscular injection, transdermally or by way of avaginal ring. Most estrogens and the synthetic progestins are orallyactive and therefore are preferably administered by that route, e.g., inthe form of a tablet, dragee, capsule or pill. If the progestin and/orestrogen is to be administered in tablet or dragee form, the latter, mayoptionally contain a pharmaceutically acceptable carrier, e.g., abinder, such as tragacanth, corn starch or gelatin; a disintegratingagent, such as alginic acid; and a lubricant, such as magnesiumstearate. Also, the estrogen and/or progestin may be deliveredtransdermally.

The estrogen and/or progestin preferably is administered withoutinterruption, since the anti-progestin alone is effective in inducingmenses, or administration thereof can be interrupted during or prior tomenses, e.g., beginning on day 1 of anti-progestin administration andfor up to about 6 days thereafter. Thus, the estrogen and progestin canbe administered uninterrupted at lower than conventional doses for up to6 months or longer, during which time, menses can be induced at adesired and preselected frequency, e.g., every 20, 30, 60, 90, 120, 150or 180 days, by administrating a menses-inducing amount of theanti-progestin 1, 2 and/or 3 days prior to the desired day of onset ofmenses.

Examples of anti-progestins which can be employed in this invention areRU 486 (“Mifepristone”, Roussel Uclaf, Paris); and “Onapristone”(Schering Ag, Berlin; U.S. Pat. No. 4,780,461) and the steroidsdescribed in the following patents and patent applications: U.S. Pat.No. 4,609,651, especially the compound lilopristone(11β-(4-dimethylamino-phenyl-17β-hydroxy-17α-(3-hydroxy-prop-1-(Z)-enyl-4,9(10)estradien-3-one); U.S. application Ser. No. 06/827,050, especially thecompounds11β-4-acetylphenyl)-17β-hydroxy-17α-(1-propinyl)-4,9-estradien-3-one and11β-(4-acetylphenyl)-17β-hydroxy-17α-(3-hydroxy-1(2)-propenyl)-4,9-estradien-3-one;U.S. application Ser. No. 07/283,632; U.S. application Ser. No.07/541,806, corresponding to published European patent application EP-A04042831; and other antigestagens e.g., U.S. Pat. No. 4,891,368. Theamount of the anti-progestin administered, in a single or in divideddoses over a 24-72 hour period typically is about 50 to 500 mg. Theminimum amount required to predictably induce menses can readily bedetermined by routine clinical experiments.

After the antiprogestin is administered, e.g., in a single dose or individed doses on the same day or on successive days, menses is usuallyachieved within about 3-4 days thereafter.

Optionally, the antiprogestin can be administered in admixture with adaily dose of the estrogen and progestin on an appropriate day or daysof the cycle, e.g., day 20 or any day thereafter, e.g., day 30, 60, 90,120, 150 and/or 180.

In its article of manufacture embodiment, this invention relates tomaterials, reagents and kits for practicing the methods of thisinvention.

In its kit aspect, this invention is directed to an otherwiseconventional multiple dosage unit article of manufacture comprising 20or 28 dosage units adapted for oral-administration. All versions containin their first 20 or more units collectively, an amount of an estrogenand a progestin effective, when one dosage unit thereof isself-administered on 21 successive days, to block folliculogenesis forone cycle but which is less than the amount thereof effective to avoidincidents of bleeding problems. The last dosage unit of the 21 dosageunits version and the 22nd dosage unit of 22 and 28 dosage unitsversions contain an amount of an antiprogestin effective to preventincidents of bleeding problems and induce menses. The 22nd to 28thdosage units of the 28 dosage units version either contain, like thefirst 21 dosage units, low dosage amounts of estrogen and progestin.

Preferably, the dosage units containing the estrogen and progestinand/or antiprogestin are adapted for oral administration but canalternatively be adapted for sub-lingual, rectal, vaginal or topical (onthe skin) application. Preferably also, units adapted for oral ingestionare in the form of tablets, capsules or dragees. Preferably further, theantiprogestin is contained in the same unit or units containing theestrogen and the progestin.

The pharmaceutical compositions employed in the process of thisinvention will usually contain the anti-progestin in conjunction with aconventional, pharmaceutically acceptably carrier. Usually, theeffective dosage of the anti-progestin is from about 1.0 to about 10milligrams per kilogram of the body weight of the host when givenorally. Effective dosages will vary with the selected mode ofadministration and the particular species of mammal being treated.

In a pharmaceutical composition aspect, this invention relates to anoral dosage form, e.g., pill, tablet, caplet or capsule or liquid,containing a menses-inducing amount of the antiprogestin, in admixturewith the amount which is orally contraceptive, when correspondingamounts thereof are ingested by a gonadal female mammal on 21 successivedays, of an orally active estrogen or an orally active progestin and,optionally, a conventional pharmaceutically acceptable carrier, e.g.,binder, filler or diluent in the case of a solid dosage form, or anaqueous or alcoholic liquid, e.g., as described herein above. Thecomposition is intended to be ingested by an individual on a continuousor sequential estrogen and progestin contraceptive regimen e.g.,conventional combined daily oral estrogen and progestin ingestion, whena menses is desired.

The pharmaceutical composition of this invention permits dispensing theoral estrogen/progestin in bulk forms, e.g., in bottles of 30, 60 or 100tablets or capsules or in bottles of liquid, since the daily dosagethereof can remain unchanged throughout the period of administration.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and unless otherwise indicated, allparts and percentages are by weight.

The entire texts of all applications, patents and publications, citedabove and below, are hereby incorporated by reference.

EXAMPLES Example I Intermittent Antiprogestin Administration DuringContinuous Ultra Low Dose Contraception

Primates

Thirty-four adult female rhesus monkeys (Macaca mulatta) having regularpresumptively ovulatory menstrual cycles (28.7±3.4 days for the monthprior to study entry) were selected. Their duration of spontaneousmenses was 3.7±1.6 days. These primates are worthy laboratory surrogatesfor investigations pertinent to human oral contraceptive use because ofextensive physiologic similarities to the functions of thehypothalamic-pituitary-ovarian-uterine axis in women. See Hodgen, G D.,“Fertil Steril 1982; 38:281; Danforth D R. et al., “Contraception” 1989;39:321; and van Uem J F H M, et al., “Contraception” 1989; 40:171.

Mean body weight of the monkeys was 5.8±1.6 kg (X±SEM). They were housedindividually in a controlled environment (12 hours of light and 23° C.).Their diet was a commercial primate food (Purina, St. Louis, Mo.) withwater ad libitum.

The Eastern Virginia Medical School maintains a fully accredited animalresearch facility which complies through its Animal Care and UseCommittee with the review standards set forth in the National Institutesof Health's “Guide for Care and Use of Laboratory Animals”, the PublicHealth Services' “Principles for the Care and Use of LaboratoryAnimals”, and the United States Department of Agriculture'sImplementation Regulations of the 1985 amendments for the Animal WelfareAct.

Study Design

The study was conducted in two parts: Part I was an adaptation intervalof three oral contraceptive treatment cycles, each of which consisted oforal medication by gavage for 21 days followed by 7 no treatment days,thus mimicking the traditional regimen of commercial oral contraceptivepill packages. This design assured that all (32 monkeys completed thecourse) individuals would be exposed during the initial adjustmentinterval, to a medication regimen for which prior human data has shown atransiently higher incidence of breakthrough bleeding than occurs amonglonger-term contraceptive users. See Gray (1990); Culbey et al. (1982),supra. Vaginal swabs (cotton tipped applicators moistened in 0.9%saline) and other hands-on procedures were performed daily between 7 and9 a.m. to detect bleeding (recorded subjectively as spotting, moderateflow or overt menses). In treatment cycle 2 only, but including theantecedent week, daily blood samples were collected from a femoral veinunder light ketamine anesthesia (30 to 50 mg, in Vetalar, Parke Davis,Morris Plains, N.J.). Serum was harvested and frozen (−15° C.) untilradioimmunoassay of estradiol and progesterone (Danforth et al. (1989);van Vem et al., (1989) supra, which was completed before starting PartII of the study, thereby insuring that ovulation inhibition was achievedby the ultra low dose regimens.

In Part II, 30 of these primates were randomly assigned to fivetreatment groups of six each: (1) the oral contraceptive medicationemployed in Part I was continued (21+7 day regimen) for 6 months; (2)continuous (no “pill-free” interval) daily estrogen-progestinmedication, with combined single day oral administration of anantiprogestin (RU 486) on treatment days 30, 60, 90, 120, 150, and 180;(3) same as group 2, except that the progesterone antagonist was givenonly on days 60, 120, and 180; (4) same as group 2, except that RU 486was given only on days 90 and 180; and (5) 180 days of continuousestrogen-progestin daily therapy, but without any antiprogestintreatment. Daily monitoring to detect vaginal blood, as in Part I above,was discontinued at 187 days. Femoral blood was collected once weeklythroughout in order to identify potential breakthrough ovulation viaprogesterone elevations; serum values above 1.0 ng/ml were consideredindicative of ovarian luteal function and possible ovulation. Likewise,these same specimens were analyzed for estradiol levels in order tomonitor ongoing endogenous estrogen biosynthesis. Two monkeys, in groups1 and 3, respectively, were dropped from the ongoing protocol, one dueto a skin rash and the other because of a thumb infection requiringtopical treatment. Neither incident is believed to be related to thehormonal treatments.

Medications

To achieve ultra low dose oral contraception and to adjust thecommercial medication used to the smaller (than human) body weight ofthese laboratory primates, an oral dose of 1.2 μg/day of ethinylestradiol and 0.06 mg/day of norethindrone acetate was employed. Thiswas achieved by grinding to a powder a commercially available pill(“Loestrin 1/20” in a conventional 21 day pack, Parke Davis, MorrisPlains, N.J.), contained 1 mg of norethindrone acetate and 20 μg ofethinyl estradiol per tablet.

In the Part II cycle, cycle RU 486 “(Mifepristone”, Roussel Uclaf,Paris) was administered intermittently as single 50 mg tablets incombination with the continuous estrogen-progestin oral contraceptiveregimen, except the group 1 and group 5 animals. Previous studies hadindicated that this dose of RU 486 would be sufficient to displacenatural progesterone from endometrial, myometrial and cervicalreceptors, thereby inducing prompt (usually within 48 hours) andcomplete sloughing of both uterine fundal and isthmic tissue, comparableto spontaneous menstruation. See Healy D L, et al., “Fertil Steril”1983; 40:253; Danforth D R et al., Contraception 1989; 40:199. Becausethe estrogen and progestin components were already combined, progestinwas included even during the intervals of RU 486 administration.

In terms of comparison to human dose equivalents, the daily dosereceived by the monkeys, with a monkey's body weight about 6 kg and awoman's at 60 kg, was about 12 μg of ethinyl estradiol and 0.6 mg ofnorethindrone acetate. Thus, this ultra low dose oral contraceptiveformulation presented a 40% reduction in daily estrogen-progestinexposure compared to one of the lowest dose combination oralcontraceptives commercially available today in America or Europe. Eventaking into account that when a continuous ultra low dose regimen wasused, versus the traditional 21+7 day protocol, there would be 92 moretreatment days on an annualized basis, the treatment reduced the annualrate of exogenous estrogen-progestin exposure by more than 20%.

Statistical Evaluations and Results

Differences between group results in study Part I, calculated as themeans and standard errors, were compared using the F statistic, testingat P<0.05 level of significance.

Although two of the menstrual factors monitored (breakthrough bleedingrates and duration of withdrawal (“pill-free”) menses did not reveal anysignificant differences (P>0.05), certain trends were observed, viz.,(1) the breakthrough bleeding rates were noticeably lower in cycles 2and 3; and (2) the duration of withdrawal menses in the “pill-free”interval was slightly less each month. In turn, the incidence ofwithdrawal amenorrhea (the third menstrual factor which was monitored)at the time of expected withdrawal menses did increase significantly(P<0.05) in treatment cycle 3 versus 1. Circulating levels of estradioland progesterone reflected indirectly the inhibitory actions of theestrogen-progestin medication on pituitary gonadotropin secretion.Although serum estradiol rose clearly during the “pill-free” intervalsadjacent to the treatment days in cycle 2, follicular maturation wascurtained by reinstitution of medication, as indicated by highest levelsaround 60 pg/ml without therapy and suppression to near 25 pg/ml on day21. Since serum progesterone levels remained at or near the lowerdetection limits of the assay throughout, the data firmly indicate thatovulation probably was blocked reliably in all 32 monkeys.

Data derived from Part II of the study was listed by treatment groupwith the profiles of endometrial bleeding through six treatment cyclesto 180 days. Mean (+SEM) number of days for breakthrough bleeding ormenses was calculated by dividing the total number of incidents recorded(per treatment cycle in the case of group 1 or 30 days intervals forgroups 2 to 5) by the number of individuals observed in the group. Inthe tabulation of data, menses (withdrawal or induced bleeding atexpected intervals) was scored for vaginal blood detected within the“pill free” interval for group 1 or within seven days after theintermittent administration of RU 486 during continuous ultra low doseoral contraception (groups 2 to 4). Similarly, failure to observevaginal bleeding during these times of expected menses, eitherwithdrawal of the oral contraceptive medication or soon after giving theprogesterone antagonist, was scored as withdrawal amenorrhea.

For group 1, the incidence of breakthrough bleeding changed little fromthe 1st to 6th treatment cycle. However, the data overall obtained inPart II compared to that in Part I showed a 2.4 fold reduction (P<0.05)in the breakthrough bleeding rates, progressively. Statisticalsignificance (P≦0.05) was reached also in treatment cycles 3 and 6 ofPart II versus treatment cycle 1 of Part I.

For groups 2 to 4 in association with the intermittent single doses ofRU 486 at 30, 60, or 90 days intervals, the overall breakthroughbleeding incidence was reduced by 57% (P<0.05) when the statisticalcomparison was made for total combined data from groups 2 to 4 versusgroup 1. However, group 5 manifested a unique response to continuousultra low dose oral contraception. The frequency of breakthroughbleeding rose moderately in the 5th and markedly in the 6th 30-dayinterval compared to all other study groups (P<0.05).

With regard to pill withdrawal or RU 486 induced menses, the ultra lowdose oral contraceptive, administered in a traditional 21+7 day regimen,resulted in fewer (P<0.05) days of menstrual flow than in thepretreatment spontaneous menstrual cycle (1.7±0.5 days, overall versus3.7±1.6 days, respectively); menses after RU 486 was of longer duration(3.1±0.8 day; P<0.05) than with the interrupted pill cycle alone. Therewere no significant differences in bleeding profiles among RU 486treated groups (P>0.05). Lastly, those primates receiving anuninterrupted course of ultra low dose oral contraceptive medication for180 days (group−5) demonstrated a longer duration of withdrawal mensesthan other treated group (4.9±3.5 days, P<0.05). However, the degree ofindividualism observed prevented achieving statistical significance(P>0.05) from findings in the pretreatment cycle.

The incidence of amenorrhea in Part II was noticeably reduced when RU486 was added intermittently to the continuous oral contraceptiveregimen. In fact, no monkeys failed to bleed after RU 486, although forsome the presence of vaginal blood was as brief as one or two days. Incontrast, when either the 21+7 day conventional regimen or continuousadministration of the ultra low dose oral contraceptive alone was used,the incidence of amenorrhea ranged between 20 and 30% overall (P<0.05).

Throughout Part II, weekly serum progesterone levels remained below 1.0ng/ml, except for one instance when a value of 1.4 ng/ml was found.Reassay of this specimen produced a concentration of 0.26 ng/ml,suggesting that the initial value may have resulted from a spuriousassay, rather than indicating possible elevated ovarian follicular orluteal activity. Concurrently, overall serum estradiol concentrationsduring the 180 day study were 37±19, 23±7, 27±7, 22±5, 25±3 and 26±6pg/ml for groups 1 to 5, respectively, illustrating overallsignificantly (P<0.05) lower estrogen levels during continuous ultra lowdose oral contraceptive regimens, irrespective of RU 486.

These findings are consistent with the ultra low dose oral contraceptiveemployed being sufficient to block ovulation when using either aconventional regimen of 21 days of medication plus 7 “pill free” days oruninterrupted treatment for 180 days. However, the incidence of bleedingproblems, either breakthrough bleeding or withdrawal amenorrhea in the“pill free” interval was increased, irrespective of whether thetreatment regimen was the traditional 21+7 days scheme or was extendedcontinuous therapy, compared to when RU 486 was given in conjunctionwith the estrogen/progestin therapy.

Addition of the antiprogestin RU 486 intermittently at 30, 60, or 90day-intervals was associated with two improvements in the bleedingprofiles. Reduced breakthrough bleeding in the intermenstrual intervalsand reliable menstrual induction at the expected time was observed, thuseliminating withdrawal amenorrhea. Also, overall, the duration ofinduced menstrual flow was slightly greater after RU 486. Whencontinuous oral contraceptive treatment was used without RU 486, thefrequency of breakthrough bleeding rose measurably in the 5th and,especially, the 6th 30 day interval. Like-treated females that receivedsingle administrations of the progesterone antagonist at 30, 60, or 90day intervals consistently experienced the lowest (57% less)breakthrough bleeding rates compared to findings when the traditional21+7 day scheme or continuous dosing, but without the anti-progestin.

The frequency of breakthrough bleeding among women beginning oralcontraceptive use is known to be higher in the initial pill cycles thansubsequently. It is believed that this often reported observation mayreflect both a biological effect of hormonal adjustment to themedication as well as unreliable user compliance among women notexperienced with oral contraceptives. The results of the above-describedexperiments in this primate model are consistent with such opinions inpart; viz., a progressive decline in breakthrough bleeding incidence wasobserved through the initial 3 to 4 months of treatment with an ultralow dose oral contraceptive administered in a conventional 21+7 dayregimen. Although the observed absolute frequency of breakthroughbleeding was lower than that often reported in women, this may be due toenforcement of compliance experimentally on the monkeys and/or otherdifferences related to dose, regimen or species. Moreover, havingstabilized these primates on this cyclic treatment schedule for threecycles in Part I before segregating them into the five groups of Part IImay have improved our insight into the impact of RU 486 on bleedingcontrol problems associated with low dose oral contraceptive use. Notonly was RU 486 consistently related to significantly less breakthroughbleeding, but the antiprogestin reliably induced some bleeding in allinstances within 72 hours, whether administered at 30, 60 or 90 dayintervals. Without intermittent RU 486 treatment, the incidence ofamenorrhea at expected bleeding times was elevated with both the 21+7conventional regimen and the 180 day continuous treatment alone (group5). The latter data suggest that continuous oral contraceptive regimensrequire occasional sloughing of the endometrial to avert cumulativebleeding irregularities.

From the foregoing data, several possible explanations can be given forthe improved bleeding control during the continuous ultra low doseregimen of oral contraception plus intermittent RU 486. For example,serum estradiol levels were almost unvarying, hovering near 25 pg/ml,and absence of the secretory bursts of estradiol that characterize the“pill free” interval during transient “follicular escape” whentraditional 21+7 day regimens are used RU 486 treatment may act in threeways: (1) constraint by its antimitogenic properties on endometrium, onmodulating rapid endometrial proliferation; (2) negating an excessivedegree of progestin over estrogen dominance (here the ratio ofnorethindrone acetate: ethinyl estradiol is 50:1); and (3) extendedcontinuous oral contraceptive regimens that cause accumulation ofendometrial tissue, and ultimately higher breakthrough bleeding rates,can be offset by occasional sloughing of tissue.

Overall, the findings of this primate study are consistent with thefeasibility of (1) further reductions in the daily dose ofestrogen-progestin oral contraceptives; (2) continuous ultra low doseoral contraceptive regimens, wherein the daily pill-taking interval isextended to 30, 60, and 90 days without interruption; and (3) a singleintermittent dose of an antiprogestin in combination with continuousoral contraceptive regimens to reduce intermenstrual breakthroughbleeding rates and to insure avoidance of withdrawal amenorrhea, both ofwhich are known to be associated with today's lower dose oralcontraceptive regimens.

Thus, the present invention is useful in increasing oral contraceptivesafety, user satisfaction and user compliance, without comprisingcontraceptive efficacy. Moreover, because contraceptive efficacy inwomen is not sacrificed and may, in fact, be enhanced by a continuousestrogen/progestin regimen which does not require user memory ofstop-start days, as with a 21 day cycle pill package and the majorpatient compliant of menstrual nuances is meaningfully reduced byintermittent inclusion of an antiprogestin, ultra low doseestrogen/progestin oral contraceptives thus become increasinglydesirable for sexually active women from their teenage years throughmenopause.

Additionally, although some women desire from their cyclic oralcontraceptive medication a regular withdrawal menses every 4 weeks (13times annually), others would prefer a less frequent menstrual flow,assuming a safe and efficacious product designed to insure menses lessoften, such as only 4 times per year, existed. The present invention,which employs a combination of low dose estrogen-progestin pill in acontinuous regimen, in combination with an antiprogestin administeredonly at extended intervals, when a menses is desired or medicallyindicated, provides such a product.

Also, withdrawal menses in some post-menopausal women, whether usingsequential or concurrent estrogen-progestin therapy is a major cause offailed user compliance. A therapeutic regimen in accordance with thisinvention can overcome the patient disfavor of frequency cyclicalvaginal bleeding without sacrificing safety and effectiveness, by theuse of continuous estrogen replacement therapy, in conjunction with aprogestin with intermittent use of antiprogestin to shed accumulatedendometrial tissue only a few times yearly, motivates post-menopausalpatients, via less frequent menses, to remain on hormone replacementtherapy with its apparent long-term advantages to cardiovascularintegrity and bone maintenance.

In the case of hormone replacement therapy the major patient compliantof breakthrough bleeding is significantly reduced by intermittentinclusion of an antiprogestin due to its antimitotic activity which maysupplement the inhibitory effects of progestin itself on endometriumgrowth and its beneficial action on the vascular bed of the endometrium.The withdrawal bleeding following antiprogestin administration may notnecessarily occur because of the lack of endometrial transformation by aprogestin.

Example II Intermittent Antiprogestin During Estrogen and Estrogen PlusProgestin Replacement Therapy

Primates

Twenty previously ovariectomized cynomolgus monkeys (Macacafascicularis) have implanted for 281 days a single estradiol-containingsubcutaneous capsule. Estradiol release from this capsule results inserum estradiol concentrations of approximately 75 pg/ml. A subcutaneousprogesterone capsule is implanted on day 191 and remains in place untilday 281. Progesterone release from this capsule results in serumprogesterone concentrations of approximately 4 ng/ml. The study takesplace in the animal research facilities of the Eastern Virginia MedicalSchool as described in Example I.

Study Design

The purpose of this study was to evaluate to break-through bleedingprior to and after onapristone treatment in ovariectomized monkeysreceiving estrogen and estrogen plus progesterone replacement therapy.The twenty monkeys were assigned to the following four groups: Group Ireceives onapristone vehicle (saline) on days 30, 60, 90, 120, 150, 180,210, 240, 270. Group 2 receives 3 mg/kg i.m. onapristone on days 30, 60,90, 120, 150, 180, 210, 240, 270. Group 3 is treated with 10 mg/kg i.m.onapristone on the same days. Group 4 receives 30 mg/kg i.m. onapristoneon the same days. Vaginal swabs are performed daily from day 1 to 281.The primary parameter for evaluation in this study is the occurrence ofvaginal bleeding.

Results

The progressing duration of estradiol treatment results in theincreasing rate of breakthrough bleeding in the vehicle treated group(Group 1). Onapristone treatment in Groups 2-4 does not induce bleedingbut it lowers the incidence of breakthrough bleeding. Once combinedestradiol and progestin treatment has been initiated, onapristoneinduces vaginal bleeding.

Example III Hormone Replacement Therapy

Primates

Twenty ovariectomized cynomolgus monkeys were implanted subcutaneouslywith an estradiol-containing silastic capsule (3 cm length). Estradiolrelease from this capsule resulted in serum estradiol concentrations ofapproximately 75 pg/ml.

The study was undertaken in two phases.

All monkeys have reached at least day 272. The estradiol implant willremain in place to day 301. A progesterone implant (3 cm) which resultedin serum progesterone concentrations of approximately 4 ng/ml was inplace from day 185 to 210. A smaller progesterone implant (0.5 cm) willbe in place from day 210 to 294. This implant is intended to produce aserum progesterone concentration of approximately 0.7 ng/ml. The twoexperimental groups (M=10/group) were as follows:

-   -   Group 1 Onapristone vehicle (saline) on days 180, 197, 240, and        270    -   Group 2 Onapristone vehicle (40 mg/kg, im) on days 180, 197,        240, and 270

In Group 1 (vehicle) 33 days of vaginal bleeding have occurred during865 days of observation. The bleeding has occurred in three of the tenmonkeys. None of the bleeding was associated with the vehicle treatmentsnor the removal of the larger progesterone implant.

In Group 2 (onapristone, 40 mg/kg) 20 days of vaginal bleeding haveoccurred out of 800 days of observation. The bleeding has occurred inseven of the ten monkeys. Twelve of the twenty days of bleeding followedthe day 197 onapristone treatment; bleeding followed this treatment infour of the ten monkeys. Six of the twenty days of bleeding followed theday 240 onapristone treatment in one monkey. Therefore, of the days ofbleeding, only two can be classified as unscheduled bleeding(breakthrough bleeding). These two days of unscheduled bleeding occurredon days 193 and 195 in two different monkeys.

Results and Conclusions

During the control (Group 1) monkeys exhibited 33 days of unscheduledvaginal bleeding. The onapristone treated monkeys (Group 2) exhibitedonly 2 days of unscheduled vaginal bleeding. The onapristone treatmentof 40 mg/kg, im, reduced the incidence of breakthrough bleeding whichoccurs with estradiol and low-dose progesterone hormone replacementtherapy.

The results of this study show that:

1. Ovariectomized cynomolgus monkeys substituted with E₂ alone do notexhibit breakthrough bleedings (BTBs).

2. There was an increase in BTBs after an addition of low-doseprogesterone. This finding suggests that the BTBs are dependent onprogesterone.

3. Onapristone induced withdrawal-bleeding in ovariectomized monkeyssubstituted with E₂ and low-dose progesterone.

4. Onapristone reduced the incidence of BTBs in ovariectomized monkeyssubstituted with E₂ and low-dose progesterone (2 days of unscheduledbleeding (treatment group) versus 33 days of unscheduled bleeding(controls).

This invention, inter alia, relates to a method of avoiding BTBs inestrogen-HRT and estrogen/progestin-HRT by intermittent anti-progestintreatment. In the case of estrogen plus low-dosage HRT,

-   -   low-dose progestin will be introduced to suppress the        estradiol-induced mitotic activity in the endometrium        (endometrial protection without inducing negative effects on the        plasma lipids). Intermittent antiprogestin is used:    -   (1) to induce endometrial bleeding (elimination of the        endometrium additionally reduces the risk of endometrial        cancer), and    -   (2) to reduce the incidence of BTBs.

A low-dose of a progestin is defined as the amount which suppresses themitotic activity of E₂ in the endometrium but which does not producesecretory changes in the endometrium and has no negative effects on theplasma lipids (predominantly HDL). See Lobo, Regerio A. Am. I.Obstergynecol., 166 (6, part 2) 1997 (June, 1992).

Kit Example

A kit is provided which contains 28 unit doses conventional tabletsadapted for oral ingestion, each containing 12 mcg. of the estrogenethinyl estradiol and 0.6 mg of the progestin norethindrone acetate.

(a) In one embodiment, the tablets are arranged in a conventionalcircular or elongated “racetrack” oval configuration, with indiciacorresponding to the days of the week, so that compliance with the dailyintake regimen can readily be confirmed by the patient.

For an example of such products, see Berlex Laboratories “Levien-28”.The tablet arranged to be taken on the 21st or later day contains, inaddition to the ethinyl estradiol and norethindrone acetate, 500 mg. ofthe anti-progestin RU 486 (“Mifepristone”, Roussel Uclaf).

(b) In another embodiment, 20 or more e.g., 20, 23, 24, 30, 60, 90 or120, tablets containing only the estrogen and progestin or only theestrogen are packaged loosely in a container, e.g., a bottle with flatfaces or a flat metal box with a snap open top such as is conventionallyused to hold aspirin tablets, or like container. Packaged separately,e.g., in an accessible cavity in the bottle cap or in a bubble packadhesively affixed to one face of the bottle or the metal box, is atablet containing the anti-progestin alone or in admixture with theestrogen and progestin. On the package for this tablet is provided spacefor the physician (or patient) to write the day and the month when thetablet instead of (when the tablet contains both the anti-progestin andthe estrogen and progestin) or in addition to the other tablets (whenthe tablet contains only the anti-progestin) should be taken to inducemenses. The kit contains the number of tablets required to providecontinuous estrogen/progestin therapy for one menstrual cycle of 28, 30,60, 90 or 120 days duration.

(c) In another version of the above-described kits otherwisecorresponding to the first embodiment (s), amounts of the estrogen andprogestin vary, i.e., in the first 7 tablets, the amounts thereof are 35mcg. and 1.5 mg. per tablet, respectively, in the next 7, they are 30mcg. and 0.8 mg. per tablet, respectively; in the next 7, they are 20mg. and 0.6 mg. per tablet, respectively; and in the last 7, they are 5mcg. and 0.4 mg. per tablet, respectively.

(d) In variations of each of the kits described hereinabove, thenorethindrone acetate in the tablets is replaced by 25 mcg. ofgestodene.

(e) In other variations of each of the kits described hereinabove, theestrogen therein is replaced by 20 mcg. of mestranol.

(f) In other variations of each of the kits described above, theantiprogestin therein is replaced by 500 mg. of onapristone.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A method of avoiding the bleeding problems associated with administering to a female mammal for contraception dosage amounts of an estrogen low enough to create incidents of breakthrough bleeding and withdrawal amenorrhea, which comprises (a) administering the estrogen daily without interruption and (b) periodically, at intervals of at least about a month, administering to the female an amount of an antiprogestin effective to reduce or eliminate breakthrough bleeding and, optionally, to induce sloughing of accumulated endometrial tissue and thereby induce menses.
 2. A method of claim 1, wherein the estrogen and the daily dose thereof is ethinyl estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.
 3. A method of claim 1, wherein the estrogen is administered in combination with progestin.
 4. A method of claim 3, wherein the amounts of the estrogen and the progestin which are administered are effective to suppress endometrial proliferation.
 5. A method of claim 3, wherein the administration of the progestin is continued uninterrupted throughout the cycle.
 6. A method of claim 3, wherein the administration of progestin is interrupted proximate the day of antiprogestin administration.
 7. A method of claim 1, wherein the antiprogestin is administered about monthly.
 8. A method of claim 1, wherein the antiprogestin is administered orally.
 9. A method of claim 1, wherein the antiprogestin is onapristone or mifepristone.
 10. The method of claim 3, wherein the progestin is gestodene or norethindrone acetate.
 11. The method of claim 3, wherein the estrogen, the progestin and the antiprogestin are administered orally; wherein the administration of the progestin and the estrogen is continued uninterrupted throughout the cycle and wherein the estrogen and the daily dose thereof is ethinyl estradiol or estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.
 12. A kit containing at least about 20 estrogen and progestin-containing tablets, which collectively are effective when taken on successive days to achieve continuous oral contraception in a gonadal female human being but which contain amounts thereof which are too low to avoid breakthrough bleeding incidents where administration of the tablets is interrupted for a week during each monthly cycle to induce menses; and containing a tablet, arranged in the kit so as to be taken after at least 20 of the estrogen and progestin-containing tablets have been taken, which contains an amount of antiprogestin effective to induce menses.
 13. A kit according to claim 12, containing 28 of the estrogen and progestin-containing tablets, arranged to be taken sequentially with the antiprogestin-containing tablet positioned as the 20^(th) or later tablet in the sequence.
 14. A kit according to claim 12, wherein the antiprogestin is onapristone or mifepristone; and wherein the progestin is gestodene or norethindrone acetate.
 15. A kit according to claim 12, wherein the estrogen and the daily dose thereof is ethinyl estradiol or estradiol or an ester thereof in the amount of 5-15 mcg/day, mestranol in the amount of 20-25 mcg/day or conjugated estrogens in the amount of 5-15 mcg/day.
 16. A pharmaceutical composition in solid oral unit dosage form comprising amounts of an estrogen and of a progestin contraceptively equivalent to 5 mcg to 35 mcg of ethinyl estradiol and 0.5 mg to 1.5 mg of norethindrone acetate, respectively, and an amount of an antiprogestin effective to induce menses in a female human being who has ingested daily for at least 20 days corresponding amounts of the estrogen and the progestin.
 17. A pharmaceutical composition according to claim 16, containing (a) 5-15 mcg of estradiol or ethinyl estradiol or an ester thereof; (b) 0.5 to 0.75 mg norethindrone acetate or 10 to 15 mcg of gestodene and (c) 50 to 500 mg of onapristone or mifepristone.
 18. A method of contraception, comprising administering to a woman in need thereof an effective amount of estrogen, alone or in combination with an effective amount of a progestin, and an amount of antiprogestin effective to ameliorate uterine bleeding problems associated with hormone replacement therapy or contraception.
 19. A method of claim 18, wherein the antiprogestin is administered periodically.
 20. A method of claim 18, wherein the antiprogestin is administered continuously.
 21. A method of avoiding the bleeding problems associated with administering to a female mammal dosage amounts of an estrogen low enough to create incidents of breakthrough bleeding and withdrawal amenorrhea during contraception, which comprises (a) administering the estrogen daily without interruption and optionally a progestin and (b) periodically, at intervals of at least about a month, administering to the female an amount of an antiprogestin effective to reduce or eliminate breakthrough bleeding and, optionally, to induce sloughing of accumulated endometrial tissue whereby menses is induced.
 22. The method of claim 21, wherein the estrogen is administered in combination with a progestin in amounts effective to block folliculogenesis and thereby creating a contraceptive state therein and inducing menses upon the administration of antiprogestin.
 23. The method of claim 22, wherein the estrogen is administered in combination with a progestin in an amount effect to suppress endometrial proliferation.
 24. The method of claim 22, wherein the administration of the progestin and estrogen is continued uninterrupted throughout the cycle, including during menses.
 25. The method of claim 22, wherein the administration of the progestin and estrogen is interrupted proximate the day of antiprogestin administration.
 26. The method of claim 21, wherein the antiprogestin is administered about monthly.
 27. The method of claim 22, wherein the antiprogestin is administered orally.
 28. The method of claim 22, wherein the antiprogestin is mifepristone.
 29. The method of claim 22, wherein the estrogen is ethinyl estradiol.
 30. The method of claim 22, wherein the progestin is norethindrone acetate.
 31. The method of claim 21, wherein the amounts of an estrogen and a progestin administered are effective to block folliculogenesis and thereby create a contraceptive state therein; wherein the antiprogestin is administered orally about monthly; and wherein the administration of the progestin and the estrogen is continued uninterrupted throughout the cycle, including the menses.
 32. The method of claim 31, wherein the antiprogestin is administered at longer than monthly intervals.
 33. The method of claim 31, wherein the administration of the progestin is interrupted proximate the day of the antiprogestin administration.
 34. The method of claim 31, wherein the antiprogestin is administered orally.
 35. The method of claim 31, wherein the antiprogestin is mifepristone.
 36. The method of claim 31, wherein the estrogen is ethinyl estradiol or estradiol.
 37. The method of claim 31, wherein the progestin is norethindrone acetate.
 38. A kit containing at least about 20 estrogen and progestin-containing tablets, which are taken on successive days to achieve continuous oral contraception in a gonadal female human being but which contain amounts thereof which are too low to avoid breakthrough bleeding incidents where administration of the tablets is interrupted for a week during each monthly cycle to induce menses; and containing a tablet, arranged in a kit so as to be taken after at least 20 of the estrogen and progestin-containing tablets have been taken, which contains an amount of an antiprogestin effective to induce menses.
 39. A kit according to claim 38, containing 28 of the estrogen and progestin containing tablets, arranged to be taken sequentially with the anti-progestin containing tablet positioned as the 20^(th) or later tablet in the sequence.
 40. A kit according to claim 38, wherein the estrogen is ethinyl estradiol, the progestin is norethindrone acetate and the antiprogestin is mifepristone.
 41. A kit according to claim 38, wherein the estrogen is ethinyl estradiol, the progestin is gestodene and the antiprogestin is onapristone. 